9VRQ

Crystal structure of FOXC2/NFAT1 complex bound to ARRE2 DNA

Summary for 9VRQ

• Entry DOI: 10.2210/pdb9vrq/pdb
• Descriptor: Forkhead box protein C2, ARRE2-S, ARRE2-AS, ... (5 entities in total)
• Functional Keywords: transcripton factor, dna, dna binding protein/dna, dna binding protein-dna complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 57724.58

Authors

Chen, X.J.,Chen, Y.H. (deposition date: 2025-07-07, release date: 2026-05-20)

Primary citation

Chen, X.,Wu, S.,Yue, S.,Zhang, L.,Liu, X.,Dai, S.,Li, J.,Zhang, H.,Wei, H.,Guo, M.,Qu, L.,Chen, L.,Deng, Y.,Chen, Y.
FOXC2 represses NFAT1-dependent transcription through a DNA-facilitated protein-protein interaction.
Nucleic Acids Res., 54:-, 2026

PubMed Abstract: Transcription factor nuclear factor of activated T cells (NFAT) plays a central role in immune gene regulation through cooperative interactions with diverse transcriptional partners. While FOXP family members have been identified as co-regulators of NFAT1, the involvement of other FOX family proteins has remained mechanistically obscure. Here, we solved three crystal structures of NFAT1-RHR/FOXC2-DBD/ARRE DNA ternary complexes and uncovered an unexpected mode of transcriptional repression mediated by FOXC2 through direct, DNA-facilitated binding to the V-shaped groove of NFAT1's Rel-homology region (RHR). Biochemical assays revealed that DNA enhanced FOXC2-NFAT1 interaction by more than five-fold, supporting a model in which DNA acts as a structural co-factor that promotes complex formation. Mutational disruption of the FOXC2-NFAT1 interface impaired complex assembly and abrogated transcriptional repression. Functional assays further confirmed that FOXC2 suppressed NFAT1-driven transcription of multiple cytokines and chemokines, including IL2, TNF, CXCL5, and CCL2. Notably, this repressive mechanism was found to extend to other FOX proteins (FOXI1, FOXO1, and FOXK1), suggesting a broader paradigm of FOX-NFAT1 interaction. Our study defined a previously unrecognized FOX-mediated transcriptional repression mechanism and provides a structural framework for NFAT inhibition by FOX proteins, offering novel insights into the transcriptional regulation of immune-related genes.

PubMed: 42023653
DOI: 10.1093/nar/gkag367

Experimental method

X-RAY DIFFRACTION (2.8 Å)